1. Field Of The Invention
A three-pellet, pulsatile drug delivery system results in bioequivalence to Cardizem(copyright) CD. The fast release membrane (FRF) composition includes an anionic surface active agent which assures complete drug release after providing a desired lag time. The medium release fraction (MRF) and the slow release fraction (SRF) are plasticized with decreased concentrations of triethyl citrate and increased concentrations of silicone dioxide powder for improved process performance.
2. Background Of The Art
Diltiazem is a benzothiazine derivative possessing calcium antagonist activity. Diltiazem blocks the influx of calcium ions in smooth and cardiac muscle and thus exerts potent cardiovascular effects. Diltiazem has been shown to be useful in alleviating symptoms of chronic heart disease, particularly angina pectoris and myocardial ischemia and hypertension, while displaying a low incidence of side effects. The first dosage forms of diltiazem sold in the United States were tablets containing 30 mg or 60 mg of diltiazem hydrochloride sold under the tradename Cardizem(copyright) by Marion Laboratories Inc. Single oral doses of 30 mg and to 120 mg of Cardizem(copyright) tablets result in peak plasma levels about 2 to 3 hours after ingestion, and the elimination half-life is about 3 to 5 hours. Because of the relatively rapid absorption of diltiazem hydrochloride from such tablets and rapid elimination, the usual dosage regimen for immediate release tablets is for a dose to be taken three or four times daily. The need for such frequent administration may reduce patient compliance. Thus adverse therapeutic effects can arise. It thus became apparent that it would be preferable to administer diltiazem hydrochloride in a dosage form that releases the diltiazem hydrochloride much more slowly than Cardizem(copyright) tablets, so as to enable the frequency of ingestion by the patient to be reduced to once daily.
A formulation of diltiazem hydrochloride that controls the rate of release to enable once daily administration is sold in the United States under the tradename Dilacor(copyright) XR by Rhone-Poulenc Rorer Pharmaceuticals Inc. Dilacor(copyright) XR is produced as two-piece hard gelatin capsules, with each capsule containing a plurality of tablets. The 180 mg strength of Dilacor(copyright) XR contains three tablets and the 240 mg strength contains four tablets. The same tablets are used in both capsules, and each tablet contains 60 mg of diltiazem hydrochloride.
The tablets used in Dilacor(copyright) XR are made in accordance with the invention of U.S. Pat. No. 4,839,177. Each tablet is comprised of a cylindrical core containing diltiazem hydrochloride mixed with inactive ingredients that include a polymer that swells and forms a gel upon contact with aqueous fluids. Because the gel has high viscosity, it swells and dissolves only very slowly in the gastrointestinal fluids to thereby retard the rate of release of the diltiazem hydrochloride. To further retard the release, insoluble polymeric platforms are affixed to the top and bottom of the cylindrical core, thus leaving only the periphery exposed to the gastrointestinal fluid. The formulation of Dilacor(copyright) XR capsules successfully accomplishes gradual release to enable once daily dosing, but the Dilacor(copyright) XR formulation requires complex and expensive procedures to produce. In particular, production of the tablets contained in Dilacor(copyright) XR capsules requires production of cores containing the diltiazem hydrochloride and the affixing thereto of the insoluble platforms.
Another formulation of diltiazem hydrochloride suitable for once daily administration is now sold in the United States under the trademark Cardizem(copyright) CD, by Marion Laboratories Inc. Cardizem(copyright) CD is sold as capsules containing a multitude of beads. The composition of the beads contained in Cardizem(copyright) CD capsules is described in U.S. Pat. No. 5,286,497. The beads are made using core seeds to which is applied a first coating containing the diltiazem hydrochloride. Over the first coating, further coatings of polymers are applied which serve to slow down and control the rate at which the diltiazem hydrochloride is released from the beads in gastrointestinal fluids.
As explained in U.S. Pat. No. 5,286,497, there is a particular dissolution profile found to be optimum for once daily administration. This desired dissolution profile, when measured in a type 2 dissolution apparatus according to U.S. Pharmacopoeia XXII, in 0.1 NHCL at 100 rpm is as follows:
a) from 20-45% released after 6 hours;
b) from 25-50% released after 12 hours;
c) from 35-70% released after 18 hours;
d) not less than 70% released after 24 hours;
e) not less than 85% released after 30 hours;
The invention of U.S. Pat. No. 5,286,497 achieves this dissolution profile by using a mixture of beads with two differing amounts of coating. The beads with the lesser amount of coatings are referred to as xe2x80x9crapid release diltiazem beadsxe2x80x9d and the beads with the greater amount of coating are referred to as xe2x80x9cdelayed release diltiazem beadsxe2x80x9d. It is disclosed that by making each of these types of beads so as to comply with particular dissolution requirements, the mixture of the two types of beads produces the desired dissolution profile for the final composition.
A difficulty with the invention of U.S. Pat. No. 5,286,497 is that it is difficult to reliably make the two types of beads so as to get the required dissolution profile for the final mixture. In particular, the desired dissolution profile requires that the amount released must exceed 20% after 6 hours, but must not exceed 50% after 12 hours. This requires that the xe2x80x9crapid release diltiazem beadsxe2x80x9d give a sharp, step-like release of the diltiazem. Otherwise, if the amount released increases only gradually with time, beads formulated to assure that at least 20% of the diltiazem is released from the final mix after 5 hours will also cause more than 50% to be released after 10 hours, thus causing the final composition to fail to meet the defined requirements.
U.S. Pat. No. 5,968,552 discloses beads containing diltiazem hydrochloride made by processes the same as or similar to those disclosed in U.S. Pat. No. 5,286,497. However, instead of mixing only two types of beads, referred to as xe2x80x9crapid release beadsxe2x80x9d and xe2x80x9cdelayed release beadxe2x80x9d, three types of beads are made which will be referred to herein as xe2x80x9crapid release beadsxe2x80x9d, xe2x80x9cintermediate release beadsxe2x80x9d, and xe2x80x9cdelayed release beadsxe2x80x9d. By using an appropriate mixture of these three types of beads, with three different amounts of coating, it is possible to obtain the desired dissolution profile for the final mix, without the need for the individual types of beads to have the sharp step-like release profile required by the invention of U.S. Pat. No. 5,286,497.
The three bead combination (rapid release, intermediate release, and delayed release beads) of U.S. Pat. No. 5,968,552 will typically exhibit in vitro dissolution profiles as shown in the Patent when measured in 0.1 NHCL using a type 2 apparatus at 100 rpm according to U.S. Pharmacopoeia XXII. A typical profile (preferred profile) composition is Rapid Release at 3 hours 40-100% (70%), Intermediate Release at 6 hours 0 to 30% (17%), Delayed Release at 18 hours 30 to 60% (45%). The beads are provided in a manner so that the available diltiazem HCl from each set is approximately 18% in rapid release beads, about 20% in intermediate release beads, and 65% delayed release beads. This distribution cannot possibly provide bioequivalence to the biphasic plasma profile of Cardizem(copyright) CD. The release profile is only more similar to the release profile of Cardizem(copyright), as compared to that of U.S. Pat. No. 5,286,497. Even 100% release of the fast release fraction in three hours could contribute a maximum of about 28% of the diltiazem HCl (18%xc3x97the 40-100% release rate of the fast release fraction plus 15%xc3x97the 0-15% release rate in the intermediate release fraction and 67xc3x970-10% of the delayed release fraction) in three hours. This profile is asserted to provide a better dissolution profile for the final mix, without the need for individual types of beads having the sharp step-like release profile required by 5,286,497, yet still would not be expected to met the bioequivalence plasma profile of Cardizem(copyright) CD.
All three types of beads in U.S. Pat. No. 5,968,552 will usually be made by taking the same cores containing diltiazem hydrochloride and applying different amounts of polymeric coating to slow down the release. The intermediate release beads will typically have more coating than the rapid release beads, and similarly the delayed released beads will typically have more coating than the intermediate release beads. It follows that the intermediate release beads will contain a smaller percent diltiazem hydrochloride by weight than the prompt release beads, and similarly the delayed release beads will contain a smaller percent diltiazem hydrochloride by weight than the intermediate release beads. The final blend of beads will typically contain about 15% by weight rapid release beads, about 20% by weight intermediate release beads and about 65% by weight delayed released beads.
In view of the differences in percent diltiazem hydrochloride content as aforesaid, it follows that in the final blend, about 18% of the diltiazem hydrochloride content will be in the rapid release beads, about 20% in the intermediate release beads, and about 62% in the delayed release beads. By taking into account these percentages along with the typical dissolution data of the beads, the dissolution at 6 hours will be about 27%, and at 12 hours will be about 44%.
U.S. Pat. No. 5,914,134 describes Applicant""s pulsatile technology for diltiazem hydrochloride. This technology is based on drug layering of diltiazem hydrochloride in a suspension form on NuPareils(copyright) (sugar spheres, 30/35 mesh). Thereafter, the drug-layered pellets are precisely divided into three fractions for subsequent application of multiple membrane coats. Depending on the number of membrane coats applied, the delivery system is designed to deliver about 40% of the total dose in a pulsatile, site-specific manner, in the proximal segment of the small intestine and about 60% of the total dose in a sigmoidal, site-specific manner in the distal segment of the small intestine and the large intestine. The drug delivery pellet unit hydrates by controlled diffusion of water into the membrane coated, drug layered pellet. The water-soluble, porosity controlling plasticizer in the membrane coat dissolves and creates water-filled aqueous channels through which the drug permeates towards a specific segment of the digestive tract.
The plasticizer triethylcitrate in the polymeric membrane of U.S. Pat. No. 5,914,134 is responsible for driving the drug in the form of a pulse in solution form whereas the number and thickness of the membrane coatings dictate the precise time of drug delivery. The drug delivery system releases the drug from each of the three fractions in less than three hours from the beginning of drug release. It was observed that this formulation presented an apparent in-vitro insufficiency in drug release in pH 6.8 phosphate buffer. Furthermore, the innovator""s product, Cardizem(copyright) CD, is pH-independent.
The polymers poly(EA-MMA-TAMCl) 1:2:0.1 and 1:2:0.2 form films that are water-insoluble, and their permeability, which is independent of pH, depends on the content of quaternary ammonium groups. It is high when the TAMCl (trimethyl ammonium chloride) proportion is high. Aqueous dispersions of these polymers contain latex-like particles. The MFT (minimum film formation temperature) of the pure dispersions are around 40 and 50xc2x0 C. Addition of 10-20% plasticizer is necessary to reduce the MFT to below 20xc2x0 C. The addition of plasticizer is important to increase the flexibility of the films but also to lower the MFT which facilitates coating process. MFT of RS 30D value with 20% plasticizer is 5xc2x0 C. (Refer to Klaus O. R. Lehmann, Chapter 4,xe2x80x9dChemistry and Application Properties of Polymethacrylate Coating Systemsxe2x80x9d, In: Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Second Edition, Edited by James W. McGnity, Marcel Dekker, Inc., pp. 101-176). These authors state xe2x80x9cAddition of 20% plasticizer results in a considerable increase in the elongation of break whereas tensile strength at break is lowered, so that optimum film properties will be found in betweenxe2x80x9d.
Triethyl citrate decreases the glass transition temperature of quaternary polymethacrylate. It must be used in conjunction with an antiadherant such as silicone dioxide (Syloid(copyright) 244 FP) to prevent the agglomeration of quaternary polymethacrylate-coated pellets. The agglomeration problem is related to a decrease in the glass transition temperature (Tg) of quaternary polymethacrylate. It is reported in literature that the films of quaternary polymethacrylate are not sufficiently flexible. Even with 10% plasticizer they show some brittleness. Furthermore, a 20% plasticizer results in considerable increase in the elongation of break, whereas tensile strength at break is lowered. Therefore, the optimum film properties are found in between the two concentrations (10% and 20%) of the plasticizer.
To assure completeness of drug release (indicating bioequivalence of Cmax) from the fast release fraction, sodium lauryl sulfate, an anionic surfactant with pKa of 1.9 was included in the polymeric membrane. xe2x80x9cThe addition of anionic surface active agents such as sodium lauryl sulfate and sodium taurocholate to the dissolution medium (phosphate buffer at pH 6.8) led to modified release behavior when pellets coated with quaternary polymethacrylate was tested. The chloride anions of the quaternary ammonium groups of the polymer were exchanged by the more lipophilic surfactant anions (lauryl sulfate, taurocholate).xe2x80x9d K. Knop and K. Matthee, Influence of surfactants of different charge and concentration on drug release from pellets coated with an aqueous dispersion of quaternary acrylic polymers, S.T.P PHARMA SCIENCES, 796) 507-512 91997). Sodium lauryl sulfate is surface active only in the ionized state. It is only 10% ionized in 0.1N HCl. However, it still acts as an effective membrane modifier when the product developed under the current invention was tested for drug release in 0.1N HCl, which is an unexpected finding.
Other inventors observed in-vitro insufficiency in the release of diltiazem hydrochloride from polymeric membranes comprised of polymethacrylate cations, plasticizers, and antiaderants. In order to resolve this problem, a pH-independent drug delivery system of diltiazem hydrochloride was developed by adding dicarboxylic acids such as fumaric acid in the drug-loaded beads, followed by coating with plasticized polymethacrylate membrane (Eudragit(copyright) RS 30D, plasticized with water-insoluble acetyl tributyl citrate). The polymeric membrane controls drug release by hydration/swelling of the membrane, possibly due to a polymethacrylate cation-fumarate anion interaction. Narisawa, S. et al., An Organic Acid Induced Sigmoidal Release For Oral Controlled Release Preparations. Pharm. Res., Vol 11, 111-116 (1994). These authors established a relationship between t50, hours(time for 50% of drug released) and the pKa of the organic acid and concluded that the optimum range for the pKa values for achieving near-pulsatile (sigmoidal) release for slightly soluble drugs is between 4-5.
A number of U.S. Patents disclose once-daily oral delivery formulations of diltiazem hydrochloride. U.S. Pat. No. 5,439,689 is assigned to Carderm Capital L. P. This patent discloses a once-a-day oral formulation of diltiazem hydrochloride having a stair stepped release profile generated by two populations of diltiazem beads which release the drug at two different intervals of time, 3-9 hours following lag times of 3 hours and 15-21 hours following a lag time of 15 hours. Although such a formulation releases diltiazem hydrochloride over 24 hours, it relies heavily on the drug release based on organic acids, which are an irritant to the mucosa.
U.S. Pat. No. 5,529,791 is assigned to Galephar P. R., Inc., Ltd. This invention is based on a central core prepared with diltiazem salt and a wetting agent in admixture with the diltiazem salt. A central core is subsequently coated with a microporous membrane comprising at least a water-soluble or water-dispersible polymer or copolymer, and a water-, acid- and base-insoluble polymer and a pharmaceutically-acceptable adjuvant. It is apparent that this invention has not considered the absorption physiology and first-pass intestinal metabolism of diltiazem in its design.
U.S. Pat. No. 5,834,024 (assigned to F. H. Faulding and Co., Ltd.) discloses a controlled absorption diltiazem pellet formulation for oral administration comprises a core having diltiazem or a pharmaceutically acceptable salt thereof as the active ingredient. The core is surrounded by a coating having only a single layer. That layer comprises a relatively major proportion of talc and relatively minor proportion of sodium lauryl sulfate admixed with a minor proportion of a pharmaceutically acceptable, film-forming, first polymer permeable to water and diltiazem, and a major proportion of a pharmaceutically acceptable film-forming, second polymer that is less permeable to water and diltiazem than the first polymer. The core and the coating layer both exclude organic acids. The composition of the coating layer as well as the proportion of core to coating layer are effective to permit release of the diltiazem allowing controlled absorption following oral administration. By combining short lag and long lag pellets into a single formulation, the release of diltiazem is controlled over a twenty four hour period.
U.S. Pat. No. 5,834,023 (Andrx Pharmaceuticals Inc.) describes a once-a-day controlled release diltiazem formulation which includes: (a) from 20 to 50% by weight of enteric polymeric membrane coated pellets comprising a polymer membrane coated core which comprises a biologically inert core which is coated with a first layer which consists essentially of diltiazem and a polymeric binder; and a second layer which comprises a membrane comprising a pH dependent polymeric material; and (b) from 50% to 80% by weight of delayed pulse polymeric membrane coated pellets comprising a polymeric membrane coated core which comprises a biologically inert core which is coated with a first layer which consists essentially of diltiazem and a polymeric binder and a second layer which comprises a polymeric membrane which will substantially maintain its integrity in the varying pH conditions of the gastrointestinal tract but is permeable to diltiazem; and (c) a unit dose containment system.
U.S. Pat. No. 5,567,441 assigned to Andrx Pharmaceuticals, Inc., describes unit dosage forms of diltiazem hydrochloride which comprise a two fraction system, enteric polymeric membrane coated pellets and delayed pulse polymeric membrane coated pellets. This invention relies on the biological system for subject-to-subject and within subject reliability of gastrointestinal movement of enteric-coated pellets and dissolution of the complete enteric coat for bio-response in the initial phase.
Cardizem(copyright) CD is described as a once-a-day extended release capsule containing diltiazem and fumaric acid. The file history of U.S. Pat. No. 5,286,497 is believed to indicate that the formulation disclosed in that patent is the formulation for Cardizem(copyright) CD. Furthermore, the formulation for Cardizem(copyright) CD is identified in the file history of U.S. Pat. No. 5,286,497 as having a xe2x80x9cstair-step release profilexe2x80x9d which has a rapid release bead and an extended release bead.
A three-pellet, quaternary polymethacrylate-based drug delivery system results in a system with bioequivalence to Cardizem(copyright) CD. A fast release fraction (FRF) composition displays a novel release profile from previous compositions, yet provides a very strong match with Bioequivalent Plasma profiles of Cardizem(copyright) CD, the Fast Release Fraction including an anionic surface active agent which assures complete drug release after providing a desired lag time. A medium release fraction (MRF) and a slow release fraction (SRF) are plasticized with decreased concentrations of triethyl citrate and increased concentrations of silicone dioxide powder for improved process performance.
A drug-layered pellet is comprised of diltiazem and a binder (e.g., less than 0.1% by weight of the binder, preferably less than 0.05%, or less than 0.01% by weight of the binder). A three-pellet, quaternary polymethacrylate-based drug delivery system is composed of a fast release fraction (FRF), a medium release fraction (MRF) and a slow release fraction (SRF). The preferred proportion of these fractions is 35-40FRF/24-28MRF/35-40SRF (e.g., 37/26/37). The preferred weight gain of these fractions is 11-17% (12-15%, 13%), 33-45% (36-39%, 37%), and 45-52% (e.g., 48-50%, 49%) with respect to the coatings. The fast release membrane composition includes an anionic surface-active agent such as sodium lauryl sulfate. A hydrophilization of the fast release fraction (FRF) creates a microporous structure, assuring total drug release delivered as a pulse (referred to as pulsatile delivery). In the absence of such a release profile for the FRF, the product is not believed to provide a bioequivalent plasma release profile compared to that of Cardizem((copyright) CD.
The medium release fraction (MRF) and the slow release fraction (SRF) may be plasticized with suitable concentrations of plasticizer such as triethyl citrate for optimum film coating performance. Several studies were conducted prior to arriving at this conclusion. When the triethyl citrate concentration was 20%, a talc concentration of 20% and a Syloid(copyright) concentration of 2% (based on dry quaternary polymethacrylate weight), the fluidization patterns could not be optimized with changing fluidization plates, partition heights, and optimized spray patterns by changing nozzle positions and apertures. A decrease of triethyl citrate to 16% (e.g., 14-18% or 15-17%) and a simultaneous increase of Syloid(copyright) to 5% (e.g., 3.5-6.5% or 4-6%, based on dry quaternary polymethacrylate weight) resulted in a highly efficient, reproducible, and scalable film coating operation.